PURPOSE:Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous stem-cell transplantation (ASCT)-often because of age or frailty-have limited opportunities to receive multiple effective lines of therapy, underscoring the need for novel frontline strategies. METHODS:In this phase II, open-label, single-arm trial (ClinicalTrials.gov identifier: NCT05860036), patients received 3-4 cycles of protocol-allowed induction, followed by B-cell maturation antigen (BCMA) CAR-T infusion, and subsequent consolidation and lenalidomide maintenance. The primary end point was the rate of minimal residual disease (MRD) negativity (10-5) at Month three postinfusion. RESULTS:Between April 4, 2023, and December 26, 2024, 43 patients were screened, 40 were enrolled, and 36 received infusion (median age, 68 years [46-75]). In the infused cohort, the MRD negativity rate at Month three postinfusion was 100% (36 of 36; 95% CI, 90.3 to 100.0). With a median follow-up of 15.8 months postinfusion (range, 4.3-26.0), no MRD recurrence was observed. The complete response rate (CRR) increased from 33.3% (12 of 36; 95% CI, 18.6 to 51.0) preinfusion to 69.4% (25 of 36; 95% CI, 51.9 to 83.7) at Month 3% and 94.4% (34 of 36; 95% CI, 81.3 to 99.3) at last follow-up. The most common grade 3 to 4 adverse events were transient cytopenia, including lymphopenia (100%), neutropenia (88.9%), leukopenia (80.6%), thrombocytopenia (19.4%), and anemia (8.3%). Cytokine release syndrome occurred in 52.8% of patients (all grade 1 to 2), immune effector cell-associated neurotoxicity in 5.6% (all grade 1), and infections in 30.6% (grade ≥3 in 19.4%). No deaths or disease progressions occurred by cutoff. CONCLUSION:Frontline BCMA CAR-T therapy induces deep, rapid, and durable remissions with a manageable safety profile in the NDMM population ineligible for or not proceeding to ASCT. These findings support its investigation as a potentially practice-changing strategy for this population.

Minimal residual disease (MRD) negativity is a well-established prognostic marker in multiple myeloma (MM), yet the clinical relevance of MRD response timing and duration remains unclear, particularly in real-world settings. We retrospectively analyzed 1048 newly diagnosed MM patients from the National Longitudinal Cohort of Hematological Diseases in China (NICHE) between 2012 and 2023, with a total of 5406 MRD assessments. A longer time to best MRD response (> 6 months) was significantly associated with improved progression-free and overall survival, especially among those with persistent MRD positivity but stable low-level disease burden. Early responders were more likely to exhibit high tumor burden and high-risk cytogenetic abnormalities. Notably, a prolonged MRD duration (≥ 36 months) predicted favorable outcomes regardless of MRD negativity status. Integrating response timing and duration identified a "Late + Durable" MRD pattern consistently associated with the best prognosis, even in patients with persistent MRD positivity, high-risk cytogenetics, or without ASCT. These findings highlight the prognostic significance of longitudinal MRD monitoring beyond single-timepoint assessments. A slow but durable MRD response may overcome adverse biological features and support individualized risk stratification, therapeutic decisions, and long-term disease monitoring in MM.

e19571 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved rapidly over the past two decades. We aimed to describe temporal trends in treatment patterns and clinical outcomes among patients in China. Methods: This retrospective cohort study utilized electronic medical record data from the National Longitudinal Cohort of Hematological Diseases in China. Eligible patients were ≥18 years at diagnosis and received ≥ 4 cycles induction therapy. Patients were excluded if previously treated for MM. Patients were followed until death, study end (June 30, 2023), or last follow-up via telephone. OS and PFS were estimated by Kaplan–Meier methods. Age group stratified Cox proportional hazards regression was performed to identify prognostic factors for survival. Results: A total of 1,622 patients were included. Median age was 57.0 years, and 18.4% were aged >65 years. Most patients were male. At diagnosis, 41.8% had ISS stage III disease. IgG was the predominant subtype, and high-risk cytogenetic abnormalities were present in 24.1% of patients. Induction therapy shifted from mainly chemotherapy to proteasome inhibitor–based regimens by 2009, and to PI+IMiD-based combinations by 2019. By 2023, about 60% of patients received PI+IMiD-based induction and 30% received anti-CD38 antibody–based induction. Utilization of autologous stem cell transplantation (ASCT) also increased steadily over time, ranging from 22% to 48% annually. With median follow-up of 35.6 months, survival improved steadily over time: median PFS increased from 32.3 months (95% CI: 26.7–38.9) in 2008–2012 to 33.6 months (95% CI: 30.7–36.7) in 2013–2017, and to 48.0 months (95% CI: 44.6–52.5) in 2018–2023, while median OS rose from 78.5 months to 85.6 months to not reached. Advanced ISS stage and high-risk cytogenetics were linked to poorer clinical outcomes. In contrast, ASCT and the use of PI+IMiD-based or CD38 antibody–based induction regimens independently correlated with improved PFS and OS. Among patients aged >65 years, treatment pattern shifts were similar to those in the overall cohort, with increasing use of PI+IMiD-based and anti-CD38 antibody–based induction in recent years. Since 2016, roughly 10% of older patients received ASCT. Improvements in PFS and OS across time periods were likewise observed in this age group as well. Conclusions: Over two decades, NDMM treatment in China has transitioned from chemotherapy-based regimens to widespread use of PI+IMiD combinations and increasing use of anti-CD38 antibodies, and expanding application of ASCT. These advances have driven meaningful improvements in PFS and OS across the study period. Similar trends were observed among patients aged >65 years. Continued efforts to expand access to novel agents and optimize treatment strategies are essential to sustain and accelerate these gains.

Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein–Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.

The 2025 IMS-IMWG consensus genomic staging (CGS) system has improved genomic risk stratification in newly diagnosed multiple myeloma (NDMM), yet does not capture whether high-risk clones have acquired a disseminated phenotype. We investigated whether circulating tumor cells (CTC) refine CGS and enable longitudinal residual disease monitoring. We retrospectively analyzed 631 MM patients from the NICHE cohort (NCT04645199) who underwent CTC assessment across disease phases. Among 410 patients assessed at diagnosis, CTC were detectable in 63.9% and correlated with both bone marrow plasma cell infiltration and accumulation of high-risk cytogenetic abnormalities. In 359 NDMM patients with adequate follow-up, a cohort-derived CTC threshold of 0.38% independently predicted inferior progression-free survival (PFS) after multivariable adjustment. Importantly, CTC refined prognostic stratification specifically within the CGS high-risk subgroup. Patients with CGS high-risk/CTC-high disease had the shortest PFS, thereby defining a disseminated genomic high-risk phenotype comprising 12.4% (39/314) of evaluable NDMM patients. In follow-up cohorts, detectable CTC were associated with inferior outcomes in 127 patients assessed during non-progressive disease states, whereas combined CTC and bone marrow minimal residual disease assessment stratified outcomes in 120 patients with paired measurements. Overall, CTC-integrated CGS supports minimally invasive baseline risk stratification and longitudinal disease monitoring.

Primary central nervous system lymphoma (PCNSL) exhibits distinct molecular features and a unique tumor microenvironment (TME) characterized by hypoxia and reduced cerebrospinal fluid glucose levels. However, the extent to which the PCNSL TME shapes the metabolic and functional states of tumor and non-tumor microenvironment cells remains largely unexplored. Utilizing single-cell multi-omic approaches, we systematically dissected tumor-TME interactions in PCNSL and showed that glucose deprivation within the TME leads to enhanced SLC2A5-mediated fructose metabolism in tumor cells and contributes to T cell dysfunction. Furthermore, hypoxia within the TME induces SLC2A5 expression in tumor-supportive macrophages through HIF-dependent transcriptional regulation, establishing SLC2A5 and its associated fructose metabolism as potential metabolic vulnerabilities in both tumor cells and tumor-supportive macrophages. In vitro and in vivo functional assays further demonstrated that genetic and pharmacologic inhibition of SLC2A5-mediated fructose uptake markedly suppressed lymphoma growth. Collectively, our study uncovers a novel potential metabolic liability targeting tumor-TME interactions in PCNSL.

Abstract Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

This study evaluated the efficacy and safety of obinutuzumab plus bendamustine (GB) as first-line treatment for indolent B-cell lymphomas. In this prospective, multicenter, single-arm trial (NCT06415708), adults with newly diagnosed indolent B-cell lymphomas—including follicular lymphoma (FL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia (WM), hairy cell leukemia variant (HCL-v), and unclassified B-cell lymphoproliferative disorder (BCLPD-U)—received six induction cycles of GB followed by 2 years of obinutuzumab maintenance in responders (⩾ partial response). The primary endpoint was overall response rate (ORR), whereas secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 220 enrolled patients (149 with FL and 71 with non-FL), 210 completed ⩾ 3 treatment cycles. At a median follow-up of 13.1 months, ORRs in the different patient subgroups were 96.6

OBJECTIVES:Talquetamab (G-protein-coupled receptor class C group 5 member D [GPRC5D] × CD3 bispecific antibody) demonstrated antitumor activity in relapsed/recurrent multiple myeloma (RRMM) in the phase I/II MonumenTAL-1 study. We report the safety profile of talquetamab in Chinese patients from MonumenTAL-1, focusing on GPRC5D-associated on-target/off-tumor adverse events (AEs). METHODS:Adult Chinese patients with heavily pretreated RRMM and measurable disease received subcutaneous talquetamab 0.4 mg/kg once weekly (QW) or 0.8 mg/kg biweekly (Q2W). Incidence, time to onset, duration, and recovery status of GPRC5D-associated AEs were reported. Data cutoffs: 29 February 2024 (QW cohort); 26 August 2024 (Q2W cohort). RESULTS:A total of 41 adult Chinese patients were included in this study (QW cohort, n = 29; Q2W cohort n = 12). Median treatment duration was 7.7 months (QW cohort) and 7.1 months (Q2W cohort); median follow-up was 16.3 and 13.9 months, respectively. GPRC5D on-target/off-tumor AEs, predominantly grade 1-2 (one grade 3 non-rash skin toxicity; QW cohort), were most commonly oral AEs (dysgeusia, dry mouth), skin AEs (rash, non-rash skin toxicity), and nail disorders; 50%-100% resolved by data cutoff. AEs were managed with supportive therapies. Talquetamab dose modification was needed in one case (grade 2 weight decrease). DISCUSSION:The generally mild GPRC5D-associated AEs were well tolerated and consistent with the known safety profile of talquetamab. Supportive management of these AEs without need for dose modification enabled prolonged treatment. CONCLUSIONS:Education of patients with RRMM on potential GPRC5D-associated AEs before starting treatment, and timely management upon experience, may ensure optimum exposure and thus maximum benefit with talquetamab.

Multiple myeloma remains incurable despite therapeutic advances. Longitudinal profiling of bone marrow and peripheral blood by Chander et al. reveals selective persistence of malignant plasma cell states, compartment-specific immune remodeling, incomplete humoral recovery after autologous stem cell transplantation, and divergent vaccine responses.

Background Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect on normal B cells. Methods In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease-negative complete response, and overall survival. Results A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. At the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd (88.2% and 88.5% vs. 77.6%), as was complete response or better (71.1% and 69.0% vs. 34.5%) and measurable residual disease-negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (hazard ratio for death, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%. Conclusions Among patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson & Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.)

Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.

Approximately 5%-10% of patients with chronic lymphocytic leukemia (CLL) develop autoimmune hemolytic anemia (AIHA). However, its pathogenesis and prognostic significance remain heterogeneous and incompletely defined. This study investigated the clinical and molecular features of CLL-associated AIHA and aimed to clarify its prognostic impact. We retrospectively analyzed baseline characteristics, first-line treatments, and survival outcomes in 1,404 patients with CLL. The incidence of AIHA was 10.4%, with 69.2% of cases classified as warm-antibody AIHA (wAIHA). CLL patients with AIHA were characterized by male predominance, advanced disease stage, IGHV4-34 usage, and other adverse biological features. Among the tested genes, DNMT3A mutations were more frequent in patients with AIHA, while MYD88 mutations were enriched in cold-antibody AIHA (cAIHA). Although AIHA conferred a significantly adverse prognostic impact on CLL outcomes, this effect was markedly attenuated with targeted therapies. Unmutated IGHV status predicted inferior outcomes in the overall CLL cohort, but not among patients with AIHA. Our findings underscore the importance of routine AIHA screening in high-risk CLL and support consideration of targeted therapies to mitigate the adverse impact of AIHA on long-term survival.

Utilization of novel Bruton tyrosine kinase inhibitors (BTKi) has become common for treating CLL/SLL patients, yet limited evidence exists on the clinical characteristics and outcomes following BTKi therapy discontinuation in China. This multicenter retrospective study analyzed 37 CLL/SLL patients in China who discontinued BTKi therapy. The mean age at discontinuation was 62.67 years, with the majority being male (67.57%). Most patients (62.16%) were relapsed/refractory (R/R) CLL/SLL patients prior to BTKi treatment, and 37.84% were treatment-naïve patients. Treatment-naïve patients were significantly younger than R/R patients (56.93 vs. 66.16 years, p = 0.005). Discontinuation reasons included resistance (48.65%), intolerance (32.43%), and other factors (18.92%). The most frequently used regimen among the post-BTKi first subsequent therapies was the anti-CD20 antibody combination therapy (52.90%). The overall disease control rate during BTKi treatment was 78.13%. The median progression-free survival (PFS) for BTKi therapy was 19.09 months, 19.09 months for treatment-naïve patients, and 14.39 months for R/R patients. The minimum median PFS was observed in patients with resistance (7.86 months). After BTKi discontinuation, median PFS was shorter: 8.87 months for first subsequent therapy and 5.32 months for second subsequent therapy. No significant difference was observed in overall survival. These findings illustrate the impact of prior treatment and discontinuation reasons on subsequent outcomes.

Multiple myeloma (MM)-induced bone disease affects not only patients' quality of life but also their overall survival. Our previous work demonstrated that the gut microbiome plays a crucial role in MM progression and drug resistance. However, the role of altered gut microbiota in MM bone disease remains unclear. In this study, we show that intestinal E. cloacae is significantly enriched in MM patients with osteolysis. Through fecal microbial transplantation and single bacterial colonization experiments in a 5TGM1 MM mouse model, we found that intestinal colonization of E. cloacae promotes osteolysis by increasing circulating ammonium levels. Elevated ammonium promotes osteoclastogenesis by increasing Trap protein levels in osteoclast precursors and by acetylating and stabilizing CCL3 protein in MM cells. Inhibition of ammonium synthesis, using E. cloacae with a deleted dcd gene, along with probiotic supplementation, alleviated osteolysis in MM. Overall, our work suggests that E. cloacae promotes osteolysis in MM by synthesizing ammonium. This establishes a novel mechanism and potential intervention strategy for managing MM with osteolysis.